AcCh is known to be a neurotransmitter in the peripheral as well as the central nervous system (CNS). Reduced function of AcCh in the CNS, probably as a result of degeneration of neurones utilizing AcCh as a neurotransmitter, is believed to be related to the etiology of various diseases such as Alzheimer's disease and Down's syndrome (R. M. Marchbanks, J. Neurochem. 39 (1982) 9-15; R. D. Terry and P. Davies, Ann. Rev. Neurosci., 3 (1980) 77; N. R. Sims, D. M. Bowen, S. J. Allen, C. C. T. Smith, D. Neary, D. J. Thomas and A. N. Davidson, J. Neurochem., 40 (1983) 503-509; E. Roberts, in Ann. New York Acad. Sci. (F. Marott Sinex and C. R. Merril, editors), 396 (1982) 165-178. Furthermore, senile dementia, which may be associated with aging, appears to be somehow related to decreased AcCh activity in the CNS, and similarly impaired learning and memory functions have been associated with decreased functions of the central AcCh-system (P. S. Anderson and D. Haubrich, Ann. Rep. Med. Chem., 16 (1981) 51-60.
Administrations of drugs which either increase the level of AcCh by blocking the enzymatic breakdown of the transmitter or directly stimulate the AcCh-receptor, AcCh-agonists, have been found to improve the cognitive malfunctions observed in patients with senile dementia of the Alzheimer type to various degrees (Christie et al., Br. J. Psych. 138 (1981) 138-146; Harbaugh et al., Neurosurgery 15 (1984) 514-518; Beller et al., Psychopharmacol. 87 (1985) 147-151; Schwartz and Kohlstaedt, Life Sci. 38 (1986); Summers et al., N. Engl. J. Med. 315 (1986) 1241-1245. Compounds capable of activating the AcCh receptors are therefore of primary interest. However, most known AcCh agonists, including AcCh itself, contain quaternary ammonium groups and, consequently, these compounds do not penetrate the blood-brain barrier (BBB) easily after peripheral administration. As a result of this, such compounds do not reach the AcCh receptors in the CNS but activate almost exclusively the peripheral AcCh receptors, which are unrelated to the diseases mentioned above, provoking various undesired effects.
Arecoline (methyl 1-methyl-1,2,5,6-tetrahydropyridine-3-carboxylate) is an AcCh agonist, which does not contain a quaternary ammonium group. Arecoline is a tertiary amine, and arecoline is capable of penetrating the BBB after peripheral administration. The ester group of arecoline is, however, very rapidly hydrolyzed in vivo, and arecoline has very weak and frequently negligible central effects after peripheral administration.
Previously, a series of 3-alkoxy-4,5,6,7-tetrahydro-isoxazolo[4,5-c]pyridine derivatives (U.S. Pat. No. 4,608,378) with potent central cholinergic activity has ben described. These compounds may be considered as bioisosters of arecoline, in which the ester group has been replaced by a 3-alkoxy isoxazole unit, which is not susceptible to hydrolysis under physiological conditions.